Most final diagnoses of cancer today are still made using the same histopathologic techniques that have been in use for the past 50 years. In-vivo optical cancer detection ("optical biopsy") holds tremendous potential as an additional tool for cancer screening, diagnosis and management. Over 15 years of study has shown that optical spectra reveal differences between normal, pre-cancerous, and malignant tissues. This proposal addresses the need for practical, cost-effective, and commercially-viable fiberoptic probes and opto-electronics that can be used to detect a wide variety of cancers in vivo, ex vivo, and in vitro. Principal targets are epithelial carcinomas of the lungs, skin, esophagus, Gl tract, cervix, and bladder. The successful implementation of probes for optical biopsy will allow physicians to perform biopsies at more sites on a screening basis, help guide surgical biopsy for improved sensitivity, and help establish surgical margins when resecting malignant tissues. Results of biopsies taken with these user-friendly probes will be immediate, allowing the practitioner to perform additional measurements if needed, and to minimize patient stress caused by delayed results. Once optical biopsies are proven clinically, they may eventually replace excisional biopsies and eliminate laboratory errors. Screening rates should go up, and cancer diagnosis and treatment costs down. More than half of the 2 million cancer cases in the US each year involve carcinomas accessible to fiberoptic probes. If the probes can be shown to work in mixed tissue types as well as epithelial tissues, needle mediated probes may also detect cancers percutaneously, for indications such as breast lumps and prostate lesions. The proposed probes use Polarized Elastic Scattering Spectroscopy (PESS) to measure differences in cellular microstructure that indicate pre-malignant or malignant growth. The technique uses low level visible light that is safe, non-ionizing, non-invasive, and painless. In Phase I, probes were developed that incorporated polarized detection. In comparison to non-polarized versions, in testing on tissue phantoms the probes were shown to strongly enhance the measurement of weak signals from a thin "epithelial" layer in the presence of a strong background signal from a "sub-mucosal" layer. In Phase II, the design of the probe system will be refined, probe production methods will be developed, and ex vivo and in vivo studies in the esophagus will be conducted. This proposal is highly symbiotic with grant C54 CA104677 awarded by the Network for Translational Research for Optical Imaging (NTROI) at the National Cancer Institute. The applicant is an industrial partner in the NTROI and is participating in activities under grant C54 CA104677. [unreadable] [unreadable]